The invention relates to the field of radiopharmaceuticals, in particular metal complexes of tetrathiol ligands and their use as radioactive pharmaceuticals for diagnostics and in endoradionuclide therapy and a method for producing said metal complexes.
Diagnostics with technetium 99m preparations are widely used for investigating the renal and hepatobiliary systems, the skeleton, the myocardium, and the brain. Radium isotopes are of interest for therapeutic use in endoradionuclide therapy. The β-emitting isotope 188Re (emax=2.12 MeV) is an attractive radioisotope for radiotherapy and radioimmunotherapy because, apart from its therapy-relevant radiation properties, it can easily be obtained carrier-free as perrhenation (ReO4) in aqueous solution from a 188W/188Re generator system [Guhlke S, Beets A L, Oetjen K, Mirzadeh S, Biersack H J, Knapp F Jr. Simple new method for effective concentration of 188Re solutions from alumina-based 188W-188Re generator. J, Nucl Med. 2000, 41(7):1271-8.]. Because of the long life of the generator, 188Re is available at low cost for routine preparation of radiopharmaceuticals for treatment for instance of tumors. Regardless thereof, in the past there have been only a limited number of rhenium preparations such as 186Re-DMSA, 186Re-DTPA, and 186Re-diphosphonate for endoradionuclide therapy. However, these compounds are inadequate for therapeutic use because their action is too non-specific.
Another limiting factor in the development of rhenium radiopharmaceuticals is the lack of suitable complex formers with which the radioactive metal can be stably coupled to biomolecules. In particular, the stability of many rhenium chelates is inadequate for therapeutic application in terms of hydrolysis, reoxidation to perrhenate and radiolysis, which occurs while releasing the radioactive metal from target-forming radiopharmacons.
Derivatives of dimercaptosuccinic acid have been suggested as agents for marking proteins and antibodies with technetium-99 and rhenium-186 or rhenium-188 (U.S. Pat. No. 5,175,256, 1992). This approach does not lead to clearly defined compounds either.
With regard to the aforesaid stability criteria, the described systems and also other systems do not satisfy the requirements for a broad in vivo application.
The object of the invention is to suggest radiolytically and metabolically stable metal complexes that are suitable for conjugation with biomolecules and to suggest a method for their production.